Lipstatin derivative - soluble fiber tablets

ABSTRACT

The present invention relates to a novel pharmaceutical composition and process for preparing swallowable rapidity disintegrating methylcellulose and lipstatin derivatives together in combination with a suitable diluent and excipients.

FIELD OF THE INVENTION

[0001] The present invention relates to a preparation containing lipaseinhibitors and soluble fibers compressed into a rapidly disintegratingtablet which meets USP disintegration standards.

BACKGROUND OF THE INVENTION

[0002] Orlistat, tetrahydrolipostatin, is a hypolipaemic lipstatinderivative, presently under development by Roche under the tradenameXenical®. Orlistat is a potent and selective inhibitor of pancreaticlipase. It also creates a fat phase in the intestine and removesendogenous cholesterol from bile in the intestine (Scrip, 1993, 1850, 12& 1996, 2135, 22; Ann Rep, Roche, 1993). The lipase inhibitors actwithin the GI tract to inhibit the enzymes which hydrolyze dietary fatto glycerol and fatty acids. This hydrolysis is the required first stepfor fat digestion, and enables the absorption of lipids and fats, andtheir subsequent utilization for energy metabolism. Inhibition of fatdigestion by lipase inhibitors such as orlistat, prevents fat absorptionand hence, the availability of calories from ingested lipid.

[0003] Orlistat prevents the absorption of about one third of the fatcontained in food (Ann Rep, Roche, 1995). The drug has undergonenumerous placebo-controlled clinical studies, involving over 5000 obesepatients. Orlistat resulted in significant weight loss and had no majoradverse side-effects. During the first year of a two year study, 3-timesas many patients on orlistat (with a moderately reduced calorie diet)lost 10% or more body weight as compared to patients treated withplacebo and diet alone. Most patients who continued into the 2nd year ofthe study kept the lost weight off (Scrip, 1996, 2188, 17; Pressrelease, Roche, May 1997).

[0004] The drug is also being studied in patients with Type II diabetes(Ann Rep, Roche, 1992). The first year results of a 2 year study haveshown that 228 patients receiving orlistat 3× daily as well as followinga mildly hypocaloric diet have lost 65% more weight than the placebocontrolled group, with almost ⅓ having lost >10% of their bodyweight(Scrip, 1996, 2135, 22).

[0005] In diet-induced obese rats, orlistat at 27 mg/kg/day caused amarked loss of body weight (65 g) and a decrease in carcass fat (54 g),despite occurrence of mild hyperphagia (1 1%). Fat absorption decreasedfrom 93-94% to 17-19%. Orlistat—treated rats showed decreases in liver(13%) and retroperitoneal (RP) pad weight and an increase in small (27%)and large (38%) intestine weight (Fed Proc, 1987, 46, 1537).

[0006] The class of lipstatin inhibitors, which includes orlistat,inhibit enzymatic cleavage of fat within the intestinal lumen andlargely prevents fat absorption from the intestine. Lipstatin inhibitorsmay be added at 0.1-100 mg ranges as a dietary additive to feedstuffs(esp. for dogs or cats) to prevent or treat adiposity and to optimizethe weight of the animal. Use of these inhibitors with water insolublefiber may further reduce fat resorption and is the subject of U.S. Pat.No. 5,540,917.

[0007] Dose of orlistat plus water insoluble fiber reduces absorption offat from the feedstuff by 1-100 (esp. 40-70) %. U.S. Pat. No. 5,540,917does however, require large amounts of crude fiber to fat as the desiredfiber content is 2-3× the fat content intake.

[0008] The lipase inhibitors act peripherally to inhibit fat digestion,and lack CNS side-effects. Their major side-effect is the potential tocause steatorrhea, anal oil leakage and incontinence, flatulence, and GIdistress.

[0009] There exists in the art, the need to develop a product whichwould allow human patients to sustain a treatment regiment of thelipostatin derivatives, but reduce the potential side effects, such asanal leakage, or at least minimize them. A combination a product whichwould reduce these side effects would also provide for an easilyadministered product, which is convenient to take and transport.

SUMMARY OF THE INVENTION

[0010] The present invention relates to a readily dispersible, rapidlydisintegrating tablet which meets United States Pharmacopoeia standardsand includes a lipstatin inhibitor, and a water soluble, non-fermentablecellulose derivative, preferably methylcellulose. The lipase inhibitorsare preferably selected from among lipstatin derivatives, such as thecompound tetrahydrolipostatin (orlistat). These two components arecompressed into a tablet which further contain suitable diluents, inpreferred w/w ratios. Preferred diluents for use with methylcelluloseare edible calcium salts, such as dicalcium phosphate, dihydrate.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The need for a safe clinically effect anti-obesity compoundappears to have been found in the lipase inhibitors, of which orlistatis one of several. The mode of action of the lipase inhibitors is by toblock fat absorption by inhibiting gastric and pancreatic lipase enzymeswhich break down fat molecules to smaller absorbable fatty acids andglycerol derivatives. When taken with a well-balanced, slightlyhypocaloric diet, these inhibitors will inhibit absorption ofapproximately 30% of ingested fat.

[0012] The weight loss obtained with clinically effective doses oforlistat are approximately the same as those obtained with CNS-actingappetite suppressant drugs, such as fenfluramine, dexfenfluramine andsibutrarmine (5-10% of bodyweight in 1 year). While these drugs havepotential CNS, and other, toxicities these are not an issue with thelipase inhibitors as they are not absorbed from the gastrointestinaltract. However, these inhibitors do have their own side-effect issueswhich are gastrointestinal tract in nature. These effects can range frommild diarrhea to faecal incontinence, as well as nausea, vomiting,flatulence, abdominal pain, liquid stools, and oily stools.

[0013] While patients may find some of these side effects tolerable,others, particularly faecal incontinence and steatorrhea, are not.

[0014] The present invention, therefore provides for a swallowable soliddosage form of a combination product which contains a bulking solublefiber, preferably methylcellulose, which is convenient to take andtransport, is preferably sugar free, and a lipstatin derivative,preferably orlistat. This tablet will be easily administered to theconsumer who will not need to carry and ingest a powder diluted withwater along with the orlistat tablet, but preferably will have thecombined tablet in one dosage form. This becomes an ideal formulation toassist in patient compliance, and to help control the undesired sideeffects of the lipstatin inhibitors.

[0015] Therefore, one aspect of the present invention is apharmaceutical composition comprising:

[0016] (a) at least one water soluble, non-fermentable cellulosederivative;

[0017] (b) at least one lipase inhibitor in an amount effective fortreating adiposity; and

[0018] (c) at least one excipient which is selected from an ediblecalcium salt; or mixtures thereof.

[0019] The lipase inhibitor is selected from: (i) a lipstatin in pureform; (ii) a biomass comprising a lipase inhibitor, the biomass beingobtained by a process of fermenting a fermentation broth comprising amicroorganism which produces the lipase inhibitor and separating thebiomass from the fermented broth; or (iii) tetrahydrolipstatin.

[0020] Suitable lipase inhibitors, such as lipstatin and analoguesthereof, tetrahydrolipstatin and N-formyl-L-leucine(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecylester may beused in this invention, and are described in EP 129 748, EP 185 359 andEP 444 482 respectively. Additional lipase inhibitors are esterastin andits derivatives found in US patent 4,189,438 and U.S. Pat. No. 4,202,824and biomasss or fermentation cakes obtained in the fermentativeproduction of lipase inhibitors, such as lipstatin or esterastin aredescribed in EP 129 748 and U.S. Pat. No. 4,189,438 whose disclosuresare incorporated herein by reference in their entirety.

[0021] In an alternative embodiment of the present invention, anotheraspect of the present invention is a pharmaceutical compositioncomprising:

[0022] (a) at least one water soluble, non-fermentable cellulosederivative;

[0023] (b) at least one lipase inhibitor in an amount effective fortreating adiposity; and

[0024] (c) at least one swellable diluent or filler, such as but notlimited to various grades of microcrystalline cellulose, such as AvicelPH101, Avicel PH 102 & Avicel PH 200; corn starch; or Starch 1500.

[0025] Preferably the diluent in this formulation is microcrystallinecellulose. A preferred size of microcrystalline cellulose is from about50 to 180 micron, more preferably about 50. Avicel PH 101 has a meanparticle size of about 50; Avicel PH 102 has a mean particle size ofabout 100; and Avicel PH 200 has a mean particle size of about 190microns. Preferably the preferred microcrystalline cellulose is AvicelPH 101.

[0026] It is noted that the ratio of methylcellulose to the swellablediluent will depend upon the diluent chosen, and is within the skill ofthe art to determine with preciseness the necessary ratios.

[0027] Suitable ratios for particular diluents are described below,however, to provide greater assistance (in % w/w) ratios:

[0028] For Methylcellulose: microcrystalline cellulose, from about 2:1to about 14:1.

[0029] Preferably, for Avicel PH 101 from about 2.2-13.5:1; for AvicelPH 102 from about 2.4-8.3:1; and for Avicel PH 200 from about 2.4-4:1.

[0030] For Methylcellulose:Corn starch from about 7.5 to about 15,preferably from about 13.5:1; and

[0031] For Methylcellulose:Starch 1500, from about 2.0 to about 5.0:1,preferably from about 2.4:1.

[0032] In addition to the above noted diluents or fillers, additionalcomponents include but are not limited to, a wetting agent, a(super)disintegrant, a binding agent, dye(s) or colouring agents, andlubricants, are preferably used to prepare a tablet that is wettedreadily, and is rapidly disintegrated in 0. 1N hydrochloric acid andwater, the USP test standard test for methylcellulose.

[0033] Preferred additional agents for these swellable diluentpharmaceutical composition are similar to those discussed below for thecompositions containing the edible calcium salts.

[0034] Another aspect of the present invention is the method for dualtreatment of adiposity and the faecal incontinence and steatorrheaassociated therewith using a compressed tablet formulation of

[0035] (a) at least one water soluble, non-fermentable cellulosederivative;

[0036] (b) at least one lipase inhibitor in an amount effective fortreating adiposity; and

[0037] (c) at least one excipient which is selected from an ediblecalcium salt; or mixtures thereof.

[0038] Another aspect of the present invention is the method for dualtreatment of adiposity and the faecal incontinence and steatorrheaassociated therewith using a compressed tablet formulation of

[0039] (a) at least one water soluble, non-fermentable cellulosederivative;

[0040] (b) at least one lipase inhibitor in an amount effective fortreating adiposity; and

[0041] (c) at least one swellable diluent or filler, such as but notlimited to various grades of microcrystalline cellulose, such as AvicelPH101, Avicel PH 102 & Avicel PH200; corn starch; or Starch 1500.

[0042] The dosage of orlistat in either the edible salt or swellablediluent formulation is recommended to be about 120 to 125 mg three timesdaily, which dosage can conveniently be formulated in a 250 to 500 mgmethylcellulose tablet as described herein. However, it is recognizedthat in some individuals a higher dosage might be necessary, such as 50to 250 mg three times daily, preferably 100-200 mg, more preferably110-150 mg.

[0043] To accommodate this dosage range with the non-fermentablecellulose a tablet containing about 40 to 70, preferably about 50 to 60mg of orlistat with about 450-500 mg methylcellulose. This wouldhopefully provide translate to a total daily dose of orlistat of 150 to750 mg/day, preferably 300 -600 mg/day, and more preferably about a doseof 330 to 450 mg/day range on mg/Kg basis (assuming a 75 Kg person) is4.4 mg/kg-day to 6 mg/Kg-day, under the most optimal conditions.

[0044] A preferred non-fermentable cellulose for use herein ismethylcellulose having a viscosity of >1000 centipoise. Lower molecularweight (mw) methylcellulose is less desirable for use in a rapidlydisintegrating tablet formulation.

[0045] By using the testing methods for methylcellulose under standardconditions, such as those found in the USP XXII, p. 894, ApparentViscosity method for Methylcellulose, or as discussed in Handbook ofPharmaceutical Excipients, APhA, a preferred methylcellulose for useherein should have a viscosity of >1000 centipoises (cps),preferably >2000 centipoises, more preferably >3000 centipoises, andmost preferably >4000 centipoise. Higher molecular weightmethylcellulose than those described is also desirable, however, thecommercially availability of this grade of methylcellulose being thelimiting feature. At present the upper limit commercially available isabout 6000 cps, which is encompassed within the scope of this invention.One presently available methylcellulose product for use herein isMethocel A4M, made by Dow Chemical Company, Midland Mich. as DowMethocel A4M, having a viscosity of about 3000 to about 5,600 cps, whichis within 75 to 140% of the desired target viscosity herein.

[0046] The edible calcium salts suitable for use herein include but arenot limited to, dibasic calcium phosphate dihydrate, calcium phosphateanhydrous, and tribasic calcium phosphate; or mixtures thereof. Apreferred edible calcium salt is the dibasic calcium phosphate dihydratesalt, which salt also provides good compressibility.

[0047] The edible calcium salt formulation may contain additionaldiluents or fillers which are preferably swellable agents (such as usedalone in the alternative formulation), and may include, but are notlimited to, various grades of microcrystalline cellulose, such as AvicelPH 101, Avicel PH 102, & Avicel PH200; Corn starch, cornstarchderivatives, such as maltodextrin; or Starch 1500.

[0048] In either formulation, if microcrystalline cellulose is added, itis preferably from about 50 to 180 microns in size, more preferablyabout 50. Avicel PH 101 has a mean particle size of about 50; Avicel PH102 has a mean particle size of about 100; and Avicel PH 200 has a meanparticle size of about 190 microns. Preferably the preferredmicrocrystalline cellulose is Avicel PH 101.

[0049] It is noted that the ratio of methylcellulose to edible calciumsalt, and additional diluents will depend upon the diluent chosen, andis within the skill of the art to determine with preciseness thenecessary ratios.

[0050] In formulating the compressed tablet suitable ratios forparticular diluents are described below (in % w/w) ratios:

[0051] Suitable ratios for particular diluents however, are describedbelow:

[0052] For Methylcellulose:Dibasic calcium phosphate, dihydrate, fromabout 2 to about 4:1, preferably from about 2.6-3.1:1;

[0053] For Methylcellulose:Calcium phosphate, anhydrous from about 2 toabout 4:1, preferably from about 3.1:1;

[0054] Methylcellulose:Tribasic calcium phosphate, WG® from about 2 toabout 4:1, preferably from about 3.1:1.

[0055] It is recognized that with the edible calcium salt, theformulation must also have an ingredient which keeps the granulestogether, i.e. a binding agent. A preferred binding agent is PVP, or thealternative agents noted below.

[0056] In addition to the above noted edible calcium salt(s), optionaldiluents or fillers, and binding agent(s), the formulation may alsoinclude additional components such as, but are not limited to, a wettingagent, (super)disintegrant(s), a second binding agent(s), dye(s) orcolouring agents, and lubricants, which are preferably used to prepare atablet that is wetted readily, and is rapidly disintegrated in 0.1Nhydrochloric acid and water, the USP test standard test formethylcellulose.

[0057] A preferred wetting agent is sodium lauryl sulfate.

[0058] A preferred lubricant is magnesium stearate.

[0059] A preferred binding agent is polyvinylpyrrolidone, or PVP, suchas Povidone 29K/32. Preferably, the PVP is present in an amount of about4 to about 6.5% w/w.

[0060] A preferred disintegrating agent is sodium starch glycolate, suchas Explotab®. Preferably, the sodium starch glycolate is present in anamount of about 3 to about 8% w/w.

[0061] As various excipients and diluents will be formulated together,and used in combination herein, suggested % w/w ratios for variousformulations are presented below. These ratios are merely illustrativeof the present invention and the skilled artisan will readily recognizehow to formulate the product of this invention with the addition ofedible calcium or the swellable diluent (where desired).

[0062] Sodium lauryl sulfate:Explotab:Dibasic calcium phosphate,dihydrate:Povidone 29K/32: Magnesium stearate include:0.38-0.40:3.5-7.9:20.6-24.8:4.0-6.5:0.5-1.0

[0063] Sodium lauryl sulfate:Explotab:Tribasic calcium phosphate WG®:Povidone 29K/32: Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0

[0064] Sodium lauryl sulfate:Explotab:Calcium phosphate, anhydrous:Povidone 29K/32: Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0

[0065] Methylcellulose:sodium lauryl sulfate (SLS), from about 60 toabout 170:1, preferably from about 155:1-170:1;

[0066] Methylcellulose:Povidone, preferably PVP 29K/32, from about 8 toabout 22:1, preferably from about 10.4:1-16.7:1;

[0067] Methylcellulose:Magnesium stearate from about 50 to about 150; 1,preferably from about 58-132:1;

[0068] Sodium lauryl sulfate:Explotab:Avicel PH 101 ®: Povidone29K/32:Magnesium stearate include:0.35-0.46:3.05-6.17:4.38-27.13:4.38-6.66:0.76-1.14

[0069] Sodium lauryl sulfate:Explotab:Avicel PH 102®: Povidone 29K/32:Magnesium stearate include: 0.35-0.46:4.9-6.17:9.21-25.53:4.38-6.66:0.76-1.14

[0070] Sodium lauryl sulfate:Avicel PH 200®: Povidone 29K/32: Magnesiumstearate include: 0.38-0.42:19.27-25.53:5.99-6.66:0.94-1.04

[0071] Sodium lauryl sulfate:Explotab:Corn starch: Povidone29K/32:Magnesium stearate include:0.36-0.38:3.66-7.07:4.35-4.68:4.354.68:0.88-0.95

[0072] Sodium lauryl sulfate:Explotab:Starch 1500®: Povidone 29K/32:Magnesium stearate include: 0.36-0.38:3.66-7.07 :24.05-25.89:4.35-4.68:0.88-0.95

[0073] Another advantageous property of the present invention is thatsome of these formulations contain calcium, such as dibasic calciumphosphate dihydrate. These formulations, for instance, will containapproximately an 80 mg/dose, anticipating formulating a 0.5 gm/tablet×2tablets/dose of methylcellulose. If desired the amount of calcium can beincreased in these tablets to provide increased therapeutic value to theconsumer.

[0074] As will readily be seen by the working examples, there arevarious combinations of intra and extragranular mixing which arepossible using the ingredients herein. All are encompassed within thescope of this invention.

[0075] Generally, the high viscosity methylcellulose, such as MethocelA4M, will first be granulated with a binder, such as povidone, a wettingagent, such as sodium lauryl sulfate, and a suitable colouring agent toform the intragranular mixture which is then granulated. These granularcomponents are then admixed with additional wetting agents, anddisintegrating agents and finally blended with lubricant. This finalgranular mixture is then blended and compressed into the tablets of thepresent invention.

[0076] Historically, cellulose ethers, such as methylcellulose andcarboxymethylcellulose have been taught as being effective bulk laxativeagents. Their mechanism of action involves increasing both the watercontent of, and the bulk content of the stool, as well as lubricatingthe stool; thereby relieving constipation.

[0077] Cellulose ethers have been administered as bulk laxatives indosage forms comprising of tablets, suspensions, and bulk powders; thelatter as sugar-free or in compositions containing high amounts ofsugar.

[0078] Other bulking may also be used in combination with this inventionfor use in reducing loose stools and diarrhea. The same property,binding water and fluid into a gel matrix, which provides stoolsoftening in constipation, will also work to reduce stool liquidity indiarrhea.

[0079] Cellulose ethers administered as suspensions in water may containhigh concentrations of sucrose or other sugars and flavors. In suchformulations, the sugar competes with the cellulose ether for availablewater, thereby preventing the cellulose ether from hydratingsufficiently to form a gel. Furthermore, the added calories from thehigh level of sugars would be disfavored for use in a weight controltherapy. Finally these suspensions are viscous, semi-gelatinous,visually unappealing to patients, and have poor palatability. Similarly,bulk powders of cellulose ethers often exhibit clumping of individualparticles, which thus remain undissolved as they pass through thedigestive tract. This could reduce bioavailability of the addedlipstatin inhibitor.

[0080] There is a common belief that tableted cellulose ethers do notreadily dissolve in the digestive tract because these cellulose ethersare highly hygroscopic. The outer portion of the tablet is said to forma gel-like hydrate that prevents the tablet from breaking up and greatlyretards the hydration of the inner portion of the tablet.

[0081] These semi-synthetic fibers, i.e. water soluble, non-fermentablecellulose derivatives (e.g., methylcellulose, ethylcellulose,carboxymethylcellulose, hydroxypropyl-methylcellulose) have been in thefood supply for decades, and are considered safe, but the beneficialclinical effects of these fibers has not been considered in the area ofTaxation as a compressed tablet, due to their failure to disintegrate.

[0082] The present invention overcomes this art recognized problem andinvolves preparation of a novel composition for the water soluble,non-fermentable fiber, in combination with a lipase inhibitor, andprocess of making such.

[0083] The tablets of this invention are prepared by a novel processinvolving a high-shear wet granulation method, followed by fluidized beddrying, milling, mixing with the other ingredients, and compression. Asnoted above, preferably, all excipients employed to prepare the tabletsof this invention are sugar-free.

[0084] This invention therefore, provides for a novel dosage form of theabove noted semi-synthetic fibers, preferably methylcellulose, with asuitable lipstatin derivative, preferably orlistat, for convenience ofadministration and for its ability to have rapid disintegration.

[0085] These tablets, in contrast to other tablets of methylcellulose,which have been previously formulated as 100% w/w methylcellulose in a0.5 gm caplet have been found not to disintegrate in 0. IN HCL solution,using a conventional dissolution apparatus even after two hours. Targettablet hardness desired is between 10 and 25, preferably 8-12 SCU; apreferred target weight of each tablet of less than 750 mg; an estimatedfriability of less than 2.0%, more preferably less than 1.0%, and targetdisintegration times below 30 minutes in water and acid (shorterdisintegration times, less than 10 minutes, more preferably less than 8minutes, in 0.1N HCl and less than 15 minutes in water, more preferablyabout 8 minutes, are preferred).

[0086] As will readily be seen by the working examples, there arevarious combinations of intra and extragranular mixing which arepossible using the ingredients herein. All are encompassed within thescope of this invention. Generally, the high viscosity methylcellulose,such as Methocel A4M, will first be granulated with the lipstatinderivative; a suitable diluent, such as microcrystalline cellulose; abinding agent, such as povidone; a wetting agent, such as sodium laurylsulfate; and optionally a suitable colouring agent to form theintragranular mixture which is granulated. These granular components arethen admixed with the lubricants, additional wetting agents,disintegrating agents, and any additional agents so desired. This finalgranular mixture is then compressed into the tablets of the presentinvention.

[0087] Therefore, one aspect of this invention is a process for themanufacture of a pharmaceutical tablet, which process comprises mixing

[0088] a) granulates comprising high viscosity methylcellulose of >3000cps; a diluent selected a diluent selected from microcrystallinecellulose, corn starch, or Starch 1500, or a mixture thereof; a lipaseinhibitor, and optionally together with an intra-granular disintegrant,and/or wetting agent, and/or colouring agent; with

[0089] b) an extra-granular disintegrant, and wetting agent, andoptionally an extra-granular lubricant and excipient(s); and

[0090] c) compressing into a tablet.

[0091] More preferablly, is the preparation of a tablet formulationwhich process comprises:

[0092] a) blending together to form an intragranular mixture highviscosity methylcellulose of >3000 cps; a diluent selected frommicrocrystalline cellulose, corn starch, or Starch 1500, or a mixturethereof; a lipase inhibitor; a lubricating agent; and optionally adisintegrant; and

[0093] b) adding to the mixture of step (a), a PVP aqueous solution, oralternatively spraying the mixture of step (a) with a PVP aqueoussolution; and preparing granulates; and

[0094] c) blending together an extragranular mixture of a wetting agent;a lubricating agent; a diluent; and a disintegrant, or a mixturethereof; and

[0095] d) compacting the granulates of step (b) with the extragranularmixture of step (c).

[0096] Yet an alternative embodiment of this invention is the admixtureof the lipase inhibitor in at step c) rather than step a).

[0097] Preferably, in this process the extragranular components includesmicrocrystalline cellulose, sodium lauryl sulfate, sodium starchglycolate, and magnesium stearate. Alternatively, the extragranularcomponents are starch, sodium lauryl sulfate, sodium starch glycolate,and magnesium stearate. A prefered range of sodium starch glycolate isfrom about 3 to about 8% w/w.

[0098] Another aspect of this invention is a process for the manufactureof a pharmaceutical tablet, which process comprises mixing

[0099] a) granulates comprising high viscosity methylcellulose of >3000cps; at least one edible calcium salt, or mixtures thereof; a lipaseinhibitor, and optionally together with an intra-granular disintegrant,and/or wetting agent, and/or colouring agent; with

[0100] b) an extra-granular disintegrant, and wetting agent, andoptionally an extra-granular lubricant and excipient(s); and

[0101] c) compressing into a tablet.

[0102] An alternative embodiment of this invention is the admixture ofthe lipase inhibitor in step b) rather than step a), and similarly tothe preferred process below.

[0103] More specifically, the process may include, preparation of atablet formulation which process comprises:

[0104] a) blending together to form an intragranular mixture highviscosity methylcellulose of >3000 cps; at least one edible calciumsalt, or mixtures thereof; a lipase inhibitor; a lubricating agent; andoptionally a disintegrant; and

[0105] b) adding to the mixture of step (a), a PVP aqueous solution, oralternatively spraying the mixture of step (a) with a PVP aqueoussolution; and preparing granulates; and

[0106] c) blending together an extragranular mixture of a wetting agent;a lubricating agent; a diluent; and a disintegrant, or a mixturethereof; and

[0107] d) compacting the granulates of step (b) with the extragranularmixture of step (c).

[0108] Therefore, another aspect of the present invention is thegranulates of the lipstatin derivative, the water soluble,non-fermentable cellulose derivative and suitable diluents andexcipients as described herein.

[0109] Therefore, another aspect of the present invention is thegranulates of the lipstatin derivative, the water soluble,non-fermentable cellulose derivative and suitable diluents andexcipients as described herein.

[0110] Yet another aspect of the present invention is the method ofrelieving faceal incontinence or anal leakage in a mammal in needthereof, which method comprises administering to said mammal, aneffective amount of a water soluble, non-fermentable cellulosederivative, preferably a high viscosity methylcellulose, compressed intoa tablet with a suitable diluent as is described above. This compositionoptionally includes an effective amount of a lipstatin derivative, suchas orlistat.

[0111] Methods of Preparation

[0112] The following examples illustrates the invention but is notintended to limit the scope thereof. All parts and percentages are byweight unless otherwise indicated. The disintegration time of theformulations described in the Tables below were obtained by using aconventional disintegration apparatus.

EXAMPLE 1

[0113] TABLE I Swallowable Methylcellulose Tablets Formula Ingredientg/tablet (% w/w) Phase A Methocel A4M 0.5000 62.64 Dibasic Calciumphosphate, dihydrate 0.0370 4.61 Sodium lauryl sulfate 0.0015 0.19Dye/Colouring agent 0.0010 0.12 Povidone 29K/32 0.0480 5.98Tetrahydrolipstatin 0.060 7.47 DI water q.s. q.s. Phase B Phase A 0.587573.14 Sodium lauryl sulfate 0.0015 0.19 Sodium starch glycolate 0.02603.24 Dibasic Calcium phosphate, dihydrate 0.1245 15.50 Magnesiumstearate 0.0038 0.47 TOTAL 0.8033 100.00

[0114] The process of preparing the rapidly disintegrating tablet ofmethylcellulose is carried out using specified quantities ofingredients, such as those mentioned in TABLE I above, using thefollowing steps:

[0115] 1. Preparation of Povidone K29/32 (PVP) Solution

[0116] The specified amount of PVP is weighed and added to the weighedquantity of water and stirred till all the PVP was dissolved completely.

[0117] 2. Preparation of Phase A

[0118] Accurately weighed amounts of Methocel A4M, calcium phosphate,dibasic dihydrate, sodium lauryl sulfate, lipase inhibitor, andcolouring agent, such as any suitable FD&C Aluminum lake, aretransferred to a Key Hi-shear granulator and mixed for about 10 minuteswith impellor speed at 135 rpm and chopper speed at 10%. The PVPsolution is sprayed onto the mixture in the granulator at a rate ofapprox. >200 mL/min. Once addition of PVP solution is complete, thechopper is stopped. The mixing is continued in the granulator tillresistance reads about 130-135 watts and the time noted to reach thatwattage. A sample is withdrawn from the wet granulation to record losson drying (% LOD). The moist granules are dried in the Aeromatic Fluidbed dryer in portions till the % LOD reading approximated 1.0-3.0%. Thetemperature of the air in the fluid bed dryer is maintained at approx.90-95 ° C. and the sample is found to be dry at an outlet airtemperature of approx. 32-52° C. The dried granules are milled through a12# screen in the Fitz Mill at a high speed. The granules are weighedand percent yield calculated. The moisture content is measured for thedry granules. A sample from the granules is withdrawn and analyzed forparticle size distribution, bulk and tap density, flow index, andmoisture studies. The granules are weighed and ingredients of Phase Bare calculated based on the weight of remaining granules.

[0119] 3. Preparation of the Final Blend

[0120] To the weighed milled granules produced in Phase A above,specified amounts of sodium lauryl sulfate, sodium starch glycolate(Explotab®), and dibasic calcium phosphate, dihydrate are added into theV-blender and mixed for about 10 minutes. Magnesium stearate is thenadded to the blend and mixed for an additional 3 minutes or so. Samplesfrom different sections of the V-blender are drawn and submitted to foranalyzing blend uniformity. A sample from the final blend is analyzedfor particle size distribution, bulk and tap density, flow index, andmoisture studies. The granules are then weighed.

[0121] 4. Compression of Methylcellulose Tablets

[0122] The final blend is charged into the hopper of a Stokes singlepunch ‘F’ tablet press and compressed into caplets with a suitabletooling. The desired target hardness is 18-21 SCU, estimated friabilitydesired is less than 1.0% and target disintegration time below 30minutes (shorter disintegration times, around 3 to 8 minutes in 0.1N HCland 8-15 minutes in water is preferred). The tablets are packaged inZiplock bags. The tablets are tested for weight variation, hardness,disintegration in acid and water, friability, moisture (% LOD),thickness, viscosity, and content uniformity.

[0123] The disintegration time for the formulation of Table 1, Example1, without orlistat, was less than 5 minutes in 0.1N HCl, and less than9 minutes in water.

EXAMPLE 2

[0124] The above formulation, Example 1, demonstrates how to prepare asuitable methycellulose rapidly disintegrating tablet which includes alipase inhibitor. As this active agent will remain constant throughoutthese examples, Examples 2 through 23 describe suitable rapidlydisintegrating tablet formulations to which an effective amount of alipase inhibitor, preferably orlistat may be added in an analogousmanner to that shown above for Example 1.

[0125] In Example 2, a formulation containing both Avicel PH 101® andExplotab®, intra and extragranularly is shown in TABLE II below.

[0126] The lipase inhibitor is shown as being added to the Phase A. Itis, however, recognized that a skilled artisan may alternativelyformulate the lipase inhibitor in Phase B using similar ingredients,ratios and amounts to those examples described herein. TABLE IISwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 60.31 Avicel PH 101 ® 0.0370 4.46 Sodiumlauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.46 Explotab ® 0.03003.62 DI water q.s. q.s. Phase B Phase A 0.6055 73.03 Sodium laurylsulfate 0.0017 0.21 Sodium starch glycolate 0.0253 3.05 Avicel PH 101 ®0.1880 22.67 Magnesium stearate 0.0086 1.04 TOTAL 0.8291 100.00

EXAMPLE 3

[0127] A formulation containing Avicel PH 101 ® intragranularly,extragranular Avicel PH 102 ® and Explotab®, intra and extragranularly,is shown below. TABLE III Swallowable Methylcellulose Tablets FormulaIngredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 59.24 Avicel PH101 ® 0.0370 4.38 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/320.0370 4.38 Explotab ® 0.0300 3.56 Dye/colouring agent 0.0040 0.47 DIwater q.s. q.s. Phase B Phase A 0.6095 72.21 Sodium lauryl sulfate0.0015 0.18 Sodium starch glycolate 0.0220 2.61 Avicel PH 102 ® 0.203524.11 Magnesium stearate 0.0075 0.89 TOTAL 0.8440 100.00

EXAMPLE 4

[0128] A formulation containing Avicel PH 101® intragranularly,extragranular Avicel PH 102® and Explotab® intra and extragranularly isshown in TABLE IV below. TABLE IV Swallowable Methylcellulose TabletsFormula Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 59.52Avicel PH 101 ® 0.0370 4.41 Sodium lauryl sulfate 0.0015 0.18 Povidone29K/32 0.0370 4.41 Explotab ® 0.0300 3.57 DI water q.s. q.s. Phase BPhase A 0.6055 72.08 Sodium lauryl sulfate 0.0015 0.18 Sodium starchglycolate 0.0220 2.62 Avicel PH 102 ® 0.2035 24.23 Magnesium stearate0.0075 0.89 TOTAL 0.8400 100.00

EXAMPLE 5

[0129] A formulation containing Avicel PH 101® intragranularly,extragranular Avicel PH 102® and Explotab® intra and extragranularly isshown below in TABLE V Swallowable Methylcellulose Tablets FormulaIngredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 60.24 Avicel PH101 ® 0.0370 4.46 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/320.0370 4.46 Explotab ® 0.0300 3.62 DI water q.s. q.s. Phase B Phase A0.6055 72.95 Sodium lauryl sulfate 0.0015 0.18 Sodium starch glycolate0.0110 1.33 Avicel PH 102 ® 0.2045 24.64 Magnesium stearate 0.0075 0.90TOTAL 0.8300 100.00

EXAMPLE 6

[0130] A formulation containing Avicel PH 101® intragranularly,extragranular Avicel PH102® and no Explotab® is shown in TABLE VI below.TABLE VI Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 67.94 Avicel PH 101 ® 0.0370 5.03Sodium lauryl sulfate 0.0015 0.20 Povidone 29K/32 0.0370 5.03Dye/Colouring Agent 0.0010 0.14 DI water q.s. q.s. Phase B Phase A0.5765 78.34 Sodium lauryl sulfate 0.0011 0.15 Avicel PH 102 ® 0.152720.75 Magnesium stearate 0.0056 0.76 TOTAL 0.7359 100.00

EXAMPLE 7

[0131] A formulation containing corn starch intragranularly,extragranular Starch 1500 and no Explotab® is shown below in TABLE VII.TABLE VII Swallowable Methylcellulose Tablets Formula Ingredientg/tablet (% w/w) Phase A Methocel A4M 0.5000 63.29 Corn starch 0.03704.68 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K/32 0.0370 4.68Dye/Colouring Agent 0.0010 0.13 DI water q.s. q.s. Phase B Phase A0.5765 72.97 Sodium lauryl sulfate 0.0015 0.19 Starch 1500 ® 0.204525.89 Magnesium stearate 0.0075 0.95 TOTAL 0.7900 100.00

EXAMPLE 8

[0132] A formulation containing corn starch intragranularly,extragranular Starch 1500 and intragranular Explotab® as shown below inTABLE VIII. TABLE VIII Swallowable Methylcellulose Tablets FormulaIngredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 61.00 Cornstarch 0.0370 4.51 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/320.0370 4.51 Explotab ® 0.0300 3.66 Dye/Colouring Agent 0.0010 0.12 DIwater q.s. q.s. Phase B Phase A 0.6065 73.98 Sodium lauryl sulfate0.0015 0.18 Starch 1500 ® 0.2045 24.93 Magnesium stearate 0.0075 0.91TOTAL 0.8200 100.00

EXAMPLE 9

[0133] A formulation containing corn starch intragranularly,extragranular Starch 1500 and intra as well as extragranular Explotab®is shown below in TABLE IX. TABLE IX Swallowable Methylcellulose TabletsFormula Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 59.88Corn starch 0.0370 4.43 Sodium lauryl sulfate 0.0015 0.18 Povidone29K/32 0.0370 4.43 Explotab ® 0.0300 3.59 Dye/Colouring Agent 0.00100.12 DI water q.s. q.s. Phase B Phase A 0.6065 72.63 Sodium laurylsulfate 0.0015 0.18 Starch 1500 ® 0.2045 24.49 Explotab ® 0.0150 1.80Magnesium stearate 0.0075 0.90 TOTAL 0.8350 100.00

EXAMPLE 10

[0134] A formulation containing corn starch intragranularly,extragranular Starch 1500 and intra as well as extragranular Explotab®(in higher amounts than shown above in Example 9, TABLE IX) is shownbelow in TABLE X. TABLE X Swallowable Methylcellulose Tablets FormulaIngredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 58.82 Cornstarch 0.0370 4.35 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/320.0370 4.35 Explotab ® 0.0300 3.53 Dye/Colouring Agent 0.0010 0.12 DIwater q.s. q.s. Phase B Phase A 0.6065 71.35 Sodium lauryl sulfate0.0015 0.18 Starch 1500 ® 0.2045 24.05 Explotab ® 0.0300 3.54 Magnesiumstearate 0.0075 0.88 TOTAL 0.8500 100.00

EXAMPLE 11

[0135] Various formulation containing Avicel PH101® intragranularly anddifferent levels of extragranular Avicel PH102® (as shown in Examples 6,7, and 8 above) may be made. TABLE XI Swallowable MethylcelluloseTablets Formula Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.500062.42 Avicel PH 101 ® 0.0370 4.62 Sodium lauryl sulfate 0.0015 0.19Povidone 29K/32 0.0480 5.99 Dye/Colouring Agent 0.0010 0.12 DI waterq.s. q.s. Phase B Phase A 0.5875 73.34 Sodium lauryl sulfate 0.0015 0.19Avicel PH 102 ® 0.2045 25.53 Magnesium stearate 0.0075 0.94 TOTAL 0.8010100.00

EXAMPLE 12

[0136] Various formulation containing Avicel PH 101® intragranularly anddifferent levels of extragranular Avicel PH102® may be made as shownbelow in Table XII. TABLE XII Swallowable Methylcellulose TabletsFormula Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 69.35Avicel PH 101 ® 0.0370 5.13 Sodium lauryl sulfate 0.0015 0.21 Povidone29K/32 0.0480 6.66 Dye/Colouring Agent 0.0010 0.14 DI water q.s. q.s.Phase B Phase A 0.5875 81.48 Sodium lauryl sulfate 0.0015 0.21 Avicel PH102 ® 0.1245 17.27 Magnesium stearate 0.0075 1.04 TOTAL 0.7210 100.00

EXAMPLE 13

[0137] Various formulation containing Avicel PH101® intragranularly anddifferent levels of extragranular Avicel PH102® may be made as shownbelow in Table XIII. TABLE XIII Swallowable Methylcellulose TabletsFormula Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 76.10Avicel PH 101 ® 0.0370 5.63 Sodium lauryl sulfate 0.0015 0.23 Povidone29K/32 0.0480 7.31 Dye/coloring agent 0.0010 0.15 DI water q.s. q.s.Phase B Phase A 0.5875 89.42 Sodium lauryl sulfate 0.0015 0.23 Avicel PH102 ® 0.0605 9.21 Magnesium stearate 0.0075 1.14 TOTAL 0.6570 100.00

EXAMPLE 14

[0138] Two formulations containing Avicel PH101® intragranularly withdifferent levels of extragranular Avicel PH 200® (shown in TABLE XIV andXV below) may be made to observe the effect on disintegration time oftablets. TABLE XIV Swallowable Methylcellulose Tablets FormulaIngredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 62.42 Avicel PH101 ® 0.0370 4.62 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K/320.0480 5.99 Dye/Coloring Agent 0.0010 0.12 DI water q.s. q.s. Phase BPhase A 0.5875 73.34 Sodium lauryl sulfate 0.0015 0.19 Avicel PH 200 ®0.2045 25.53 Magnesium stearate 0.0075 0.94 TOTAL 0.8010 100.00

EXAMPLE 15

[0139] The second of the two formulations noted above containing AvicelPH101® intragranularly with different levels of extragranular Avicel PH200® is shown below in TABLE XV. TABLE XV Swallowable MethylcelluloseTablets Formula Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.500069.35 Avicel PH 101 ® 0.0370 5.13 Sodium lauryl sulfate 0.0015 0.21Povidone 29K/32 0.0480 6.66 Dye/Coloring Agent 0.0010 0.14 DI water q.s.q.s. Phase B Phase A 0.5875 81.48 Sodium lauryl sulfate 0.0015 0.21Avicel PH 200 ® 0.1245 17.27 Magnesium stearate 0.0075 1.04 TOTAL 0.7210100.00

[0140] All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

[0141] The above description fully discloses the invention includingpreferred embodiments thereof. Modifications and improvements of theembodiments specifically disclosed herein are within the scope of thefollowing claims. Without further elaboration, it is believed that oneskilled in the art can, using the preceding description, utilize thepresent invention to its fullest extent. Therefore the Examples hereinare to be construed as merely illustrative and not a limitation of thescope of the present invention in any way. The embodiments of theinvention in which an exclusive property or privilege is claimed aredefined as follows.

What is claimed is:
 1. A pharmaceutical composition for a tabletcomprising: (a) at least one water soluble, non-fermentable cellulosederivative; (b) at least one lipase inhibitor in an amount effective fortreating adiposity; and (c) at least one excipient which is selectedfrom an edible calcium salt; or mixtures thereof.
 2. The compositionaccording to claim 1 wherein the water soluble, non-fermentablecellulose derivative is methylcellulose having a viscosity of >1000centipoise.
 3. The composition according to claim 2 wherein the ediblecalcium salt is dibasic calcium phosphate dihydrate, calcium phosphateanhydrous, or tribasic calcium phosphate; or mixtures thereof.
 4. Thecomposition according to claim 3 wherein the edible calcium salt isdibasic calcium phosphate dihydrate salt.
 5. The composition accordingto claim 2 which further comprises a binding agent which is PVP,hydroxypropylcellulose, hydroxypropyl methylcellulose, acacia, gelatin,tragacanth, pregelatinized starch, or starch.
 6. The compositionaccording to claim 2 which further comprises a disintegrating agentwhich is sodium starch glycolate, sodium carboxymethylcellulose,Ac-di-sol®, carboxymethylcellulose, veegum, alginates, agar, guar,tragacanth, locust bean, karaya, pectin, or crospovidone.
 7. Thecomposition according to claim 2 which further comprises a wettingagent, and/or a lubricating agent.
 8. The composition according to claim2 wherein the methylcellulose has a viscosity of >3000 centipoises. 9.The composition according to claim 2 wherein the methylcellulose ispresent in an amount of about 450 to about 550 mg.
 10. The compositionaccording to any of claims 1 to 9 wherein the lipase inhibitor isorlistat.
 11. The composition according to any one of claims 1 to 9compressed into a tablet.
 12. A method for the dual treatment ofadiposity and the faecal incontinence and steatorrhea associatedtherewith which method comprises administering to a mammal in needthereof a compressed tablet comprising: (a) at least one water soluble,non-fermentable cellulose derivative; (b) at least one lipase inhibitorin an amount effective for treating adiposity; and (c) at least oneexcipient which is selected from an edible calcium salt; or mixturesthereof.
 13. A pharmaceutical composition for a tablet comprising: (a)at least one water soluble, non-fermentable cellulose derivative; (b) atleast one lipase inhibitor in an amount effective for treatingadiposity; and (c) at least one swellable diluent or filler, selectedfrom microcrystalline cellulose, corn starch, or Starch
 1500. 14. Thecomposition according to claim 13 wherein the water soluble,non-fermentable cellulose derivative is methylcellulose having aviscosity of >2000 centipoise.
 15. The composition according to claim 14which further comprises a disintegrating agent.
 16. The compositionaccording to claim 15 which further comprises a wetting agent, and/or alubricating agent.
 17. The composition according to claim 16 whichfurther comprises a binding agent.
 18. The composition according toclaim 14 wherein the diluent is microcrystalline cellulose and ispresent in a ratio of methylcellulose to microcrystalline cellulose fromabout 2.1 to about 14:1.
 19. The composition according to claim 14wherein the diluent is corn starch and is present in a ratio ofmethylcellulose to cornstarch of from about 7.5 to about 15:1.
 20. Amethod for the dual treatment of adiposity and the faecal incontinenceand steatorrhea associated therewith which method comprisesadministering to a mammal in need thereof a compressed tabletcomprising: (a) at least one water soluble, non-fermentable cellulosederivative; (b) at least one lipase inhibitor in an amount effective fortreating adiposity; and (c) at least one swellable diluent or filler,selected from microcrystalline cellulose, corn starch, or Starch 1500.21. A a process for preparing a tablet formulation which processcomprises: a) blending together to form an intragranular mixture highviscosity methylcellulose of >3000 cps; a diluent selected frommicrocrystalline cellulose, corn starch, or Starch 1500, or a mixturethereof, a lipase inhibitor, a lubricating agent and optionally adisintegrant; and b) adding to the mixture of step (a), a PVP aqueoussolution, or alternatively spraying the mixture of step (a) with a PVPaqueous solution; and preparing granulates; and c) blending together anextragranular mixture of a wetting agent; a lubricating agent; adiluent; and a disintegrant, or a mixture thereof; and d) compacting thegranulates of step (b) with the extragranular mixture of step (c). 22.The process according to claim 21 wherein the admixture of the lipaseinhibitor is added in step c) rather than step a).
 23. A process for themanufacture of a pharmaceutical tablet, which process comprises mixinga) granulates comprising high viscosity methylcellulose of >3000 cps; atleast one edible calcium salt, or mixtures thereof; a lipase inhibitor,and optionally together with an intra-granular disintegrant, and/orwetting agent, and/or colouring agent; with b) adding to the mixture ofstep (a), a PVP aqueous solution, or alternatively spraying the mixtureof step (a) with a PVP aqueous solution; and preparing granulates; andc) blending together an extragranular mixture of a wetting agent; alubricating agent; a diluent; and a disintegrant, or a mixture thereof;and d) compacting the granulates of step (b) with the extragranularmixture of step (c).
 24. The process according to claim 21 wherein theadmixture of the lipase inhibitor is added in step c) rather than stepa).